Radiation-induced fibrosarcoma after breast-conserving surgery and radiation therapy for breast cancer: A case report and literature review

doi:10.21203/rs.3.rs-1648156/v3

Background: Radiation-induced sarcoma (RIS) has a 10-year incidence of 0.2-0.27% and a poor prognosis. In particular, radiation-induced fibrosarcoma has been rarer, and its incidence is 2.6-3.7% of RIS.

Case presentation: A 43-year-old woman with pT1N1M0 breast cancer underwent breast-conserving surgery, chemotherapy, radiation therapy eight years ago, and continued hormonal therapy. She complained of a hard mass palpated in her right axillary breast. Although we suspected local recurrence, core needle biopsy revealed atypical spindled tumor cells without mammary or epithelial markers. A diagnosis of fibrosarcoma was made via tumorectomy. She underwent additional enlarged surgery.

Conclusions: We report a rare case of fibrosarcoma after breast-conserving surgery and radiation therapy. Fibrosarcoma after radiation therapy for breast cancer has been reported in 30 cases, including the present case. The dead and alive cases were not significantly different in terms of age, primary breast cancer, radiation dose, and following months. Patients with breast masses after radiation therapy should be suspected local recurrence and RIS.

Fibrosarcoma

breast cancer

radiation therapy

radiation-induced sarcoma

radiation-induced fibrosarcoma

The effects of radiation after breast-conserving surgery absolutely reduce each 10-year recurrence risk or 15-year risk of breast cancer death [1]. However, radiation therapy has also been reported to cause adverse events. Anorexia, malaise, and dermatitis occur in the acute phase. In the sub-acute or late phase, there is pneumonia, cardiotoxicity, anetoderma, and secondary cancer [2–3]. As secondary cancer, radiation-induced sarcoma (RIS) has a 10-year incidence of 0.2–0.27% [4] and poor prognosis with a 5-year actuarial survival of 36–41% [4–5]. A collaborative group of early breast cancer trialists reported a ratio of rates of 2.34 (2p = 0.03) of soft-tissue sarcoma after radiation in their meta-analysis [6]. In particular, radiation-induced fibrosarcoma has been rarer, and its incidence is 2.6–3.7% of RIS [4, 7].

We report a rare case of fibrosarcoma after breast-conserving surgery and radiation therapy and review and discuss radiation-induced fibrosarcomas after breast cancer which had been reported.

A 43-year-old Japanese woman visited our outpatient clinic with a right axillary mass. She had a medical history of right breast cancer for eight years. The primary histology was an 18 mm invasive ductal carcinoma with two lymph node metastases, which had hormone receptors and lacked human epidermal growth factor receptor 2 (HER2) amplification (T1N1M0, pathological stage IIA). The patient underwent breast-conserving surgery and axillary dissection, chemotherapy with docetaxel and cyclophosphamide, and radiation therapy (50.0 Gy). During the administration of planned 10-year-tamoxifen and terminated 5-year-luteinizing hormone-releasing hormone agonist, a hard mass of 8.4 mm palpated in her right axillary breast without ulcered and protruded lesions, while no other abnormal findings were identified. Mammography revealed normal breast tissue. We suspected local recurrence of breast cancer. Findings of a core needle biopsy (CNB) revealed a proliferation of fibroblasts, but the lesion was judged to be benign. The lesion had grown for 7 months. After CNB was added, atypical spindled tumor cells without breast cancer markers (hormone receptor, HER2, and FOXA1) and epithelial markers (EMA, E-cadherin, and cytokeratin7, 8, 18, 20, AE1/AE3) were observed. As a mesenchymal marker, vimentin is highly expressed. (Fig. 1). Radiographic tests were negative for metastasis, ultrasonography scans revealed a 21.3 mm tumor with much vascular flow, and magnetic resonance imaging revealed 16 mm irregular geometries just close to the skin. We decided to perform a tumorectomy to confirm the diagnosis.

The pathological diagnosis revealed an 18 mm subcutaneous fibrosarcoma of the adult classic type (Fig. 2). In addition, skin excision was performed because the surgical margin of the skin was pathologically positive, leading to negative skin margins. The patient received a second opinion at the National Cancer Center Hospital and underwent enlarged excision.

In 1948, RIS was defined as having a history of radiation therapy, occurring in or near the radiation field, and being histologically different from primary cancer [8]. In breast-conserving therapy for breast cancer, angiosarcoma of RIS has the highest reported standardized incidence rations 26.2 [9]. Radiation therapy for breast cancer involves RIS of the chest wall, pleura, and upper extremity [10-11]. RIS has a poorer prognosis in patients over 60 years, high-grade tumors, and positive margins [5].

Radiation therapy damages deoxyribonucleic acid (DNA) in exposed cells involved in normal or malignant cells. Fibroblast cell lines repair this DNA damage through histone H2AX phosphorylation in vitro [12]. Although the mechanism of RIS occurrence has not yet been clarified, DNA damage repair might induce some gene variants associated with second malignant neoplasms [13].

We searched the keywords “breast,” “fibrosarcoma, and “radiation” in PubMed in April 2022. We also checked the references cited in the original articles and excluded articles that had no history of radiation therapy or breast cancer. Thirty cases of radiation-associated fibrosarcoma after breast cancer therapy without protruded cutaneous fibrosarcoma were identified, including our case [14-35] (Table1). All cases were detected based on the patient’s self or physical findings. They were 52.7±10.3 years old, and the duration from primary breast cancer was 9.4±4.9 years (1.3 – 17 years, median 8.0 years). Within the description, 12 patients (52%) died, and 10 (48%) were alive. Although the number of cases was small, we compared dead and alive cases using a t-test (Table2). Age, duration from primary breast cancer diagnosis, radiation dose, and following months were not significantly different.

Fibrosarcomas after breast-conserving surgery and radiation therapy are rare. Patients with breast masses after radiation therapy should be suspected not only for local recurrence but also for RIS.

RIS, radiation-induced sarcoma; CNB, core needle biopsy; DNA, deoxyribonucleic acid.

Ethical approval and consent to participate

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images complied with CARE guidelines.

Consent for publication

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Competing interests

The authors declare that they have no competing interests

Funding

Not applicable.

Authors’ contributions

HH described and designed the manuscript. HT edited the article. KK performed needle biopsy and tumorectomy. The patient was diagnosed with YT pathologically. All authors have read and approved the final manuscript.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Author details

¹Department of Breast Surgery, Kikuna Memorial Hospital, 4-4-27 Kikuna, Kouhoku-ku, Yokohama 222-0011, Japan. ²Department of Breast Surgery and Oncology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. ³Department of Integrated Diagnostic Pathology, Nippon Medical School 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. ³Diagnostic Pathology Clinic, Pathos Tsutsumi, 1551-1 Miyoshiato, Yawase-cho, Inazawa, Aichi 492-8342, Japan.

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Table 1: Cases of fibrosarcoma after radiation therapy for breast cancer.

	Reference	Reported year	Age	Primary breast cancer	Radiation Dose	Duration (year)	Location of Fibrosarcoma	Following	Prognosis
1	14	1959	63	T1N1	45Gy	5	Rib	3 years	Death
2	15	1968	58	-	+	15	Chest wall, Shoulder	-	-
3	16	1970	50	-	220kvp	6	Chest wall, Shoulder	1 year	Death
4	17	1970	43	Stage III	40Gy	14	Breast	4 months	Death
5	18	1970	53	-	39Gy	4	Chest wall	3 years	Death
6	19	1970	55	-	25Gy	10	Soulder	8 months	Death
7	19	1970	40	-	28Gy	10	Chest wall	6 months	Alive
8	20	1976	57	-	NR	16	Breast, Chest wall	-	-
9	14	1976	48	T2N0	45Gy	5.5	Supra-clavian region	2 years	Death
10	21	1977	66	-	40Gy	7	Chest wall	1.5 years	Death
11	22	1977	59	-	20Gy	12	Shoulder, Axillary region	2 years	Death
12	14	1978	58	T2N1	45Gy	4	Axillary region	13 years	Alive
13	23	1978	63	-	25Gy	14	Breast	-	-
14	24	1981	39	-	40.05Gy	11	Sternum	3.5 years	Alive
15	25	1984	43	-	50Gy	5	Chest wall	7 months	Death
16	26	1986	61	-	30Gy	17	Supra-clavian region	1 year	Death
17	27	1990	66	-	NR	15.5	Chest wall, Axillary region	1.8 years	Alive
18	28	1994	46	T1N0	60Gy	1.3	Breast	-	Alive
19	29	1996	- - -	-	NR	7	Chest wall	-	-
20				-	NR	8	Axillary region	-	-
21				-	NR	17	Pectoral muscle	-	-
22	30	1998	-	-	46+12Gy	2	Axillary region	-	Alive
23	31	1998	39	T2N2	60Gy	8	Subclavian region	34 months	Death
24			47	T1N0	45Gy	16	Chest wall	18 months	Death
25			40	T2N0	60Gy	7	Axillary region	5 months	Death
26	32	2002	42	T2N+	50Gy	17	Subclavian region	19 months	Alive
27	33	2004	72	-	50Gy	4	Chest wall	2.8 years	Alive
28	34	2006	44	T1N1	50Gy	2	Axillary region	-	Alive
29	35	2013	68	T2N0	-	6	Spine	-	-
30	Present	2022	43	T1N1	50 Gy	8	Axillary breast	-	Alive

Table 2: Comparison with cases of dead and alive cases by t-test.

	Alive n=10	Death n=12	p value
Age (years old)	50.0±12.2	51.4±9.4	0.77
Duration (years)	8.1±5.7	9.2±4.5	0.62
Radiation dose (Gy)	47.9±9.6	41.6±12.3	0.22
Following months	40.3±52.9	18.8±12.0	0.26

No competing interests reported.

Radiation-induced fibrosarcoma after breast-conserving surgery and radiation therapy for breast cancer: A case report and literature review

Status:

Version 3

Abstract

Figures

Background

Case Presentation

Discussion And Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 3